Aging Endothelial Precursor Cell Proangiogenic Function

衰老内皮前体细胞促血管生成功能

• 批准号: 6500178
• 负责人: Jay M. Edelberg
• 金额: $ 36.32万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6500178
• 关键词: Adenoviridae; aging; angiogenesis; animal old age; biotechnology; bone marrow transplantation; cardiovascular disorder prevention; gene expression; growth factor receptors; immature animal; laboratory mouse; laboratory rat; mature animal; myocardial infarction; nonhuman therapy evaluation; platelet derived growth factor; stem cell transplantation; stem cells; tissue /cell culture; transfection

Angiogenic potential in the aging heart is depressed. Preliminary studies have revealed that alterations in aging endothelial cells result in the dysregulation of a cardiac myocyte-induced platelet-derived growth factor (PDGF B)-mediated pathway that underlies the decline in senescent cardiac angiogenic activity. Recent studies have also demonstrated that the bone marrow is a source of endothelial precursor cells (EPCs) that may contribute to the regulation of angiogenic function. Specifically, it was shown that when co-cultured with cardiac myocytes, EPCs derived from the bone marrow of young adult mice (3 months old) are induced to express PDGF B, whereas cells derived from the bone marrow of aging mice (18 months old) are not. In vivo studies revealed that reconstitution of the PDGF B- dependent pathways by delivery of PDGF AB or transplantation of young bone marrow cells into intact, unirradiated aging mice restores senescent cardiac angiogenic function. Moreover, this proangiogenic pathway protects the aging heart from myocardial infarction. Taken together, these preliminary data strongly support the hypothesis that reconstitution of the PDGF B-induced pathways in EPCs derived from the aging bone marrow will restore senescent cardiac angiogenic function. The long-range goals of this project are to specifically enhance angiogenic activity in the aging heart by the molecular restoration of the activity of EPCs derived from the aging bone marrow. The critical elements of the pathways upstream of PDGF B induction will be defined and restored in older bone marrow- derived EPCs to promote the long-term reconstitution of the senescent cardiac proangiogenic pathways. In addition, the critical set of downstream genes mediating the angiogenic actions of PDGF B induction will be defined as a means of establishing molecular regimens to restrict the restoration of proangiogenic function of aging bone marrow-derived EPCs to the cardiac vasculature. The physiological significance of the elements and genes identified by these studies will be defined by their ability to promote cardiac angiogenic function and protect the aging heart from myocardial infarction. Overall this research plan will establish a foundation for development of novel approaches to exploit the potential of EPCs derived from the aging bone marrow for the treatment and possible prevention of cardiovascular diseases in older persons.

衰老心脏的血管生成潜力受到抑制。初步研究表明，衰老内皮细胞的改变导致心肌细胞诱导的血小板衍生生长因子（PDGF B）介导的途径失调，这是衰老心脏血管生成活性下降的基础。 最近的研究还表明，骨髓是内皮前体细胞 (EPC) 的来源，可能有助于调节血管生成功能。具体而言，研究表明，当与心肌细胞共培养时，源自年轻成年小鼠（3个月大）骨髓的EPC被诱导表达PDGF B，而源自老年小鼠（18个月大）骨髓的细胞则不会表达PDGF B。 体内研究表明，通过输送PDGF AB 或将年轻骨髓细胞移植到完整的、未受辐射的衰老小鼠体内来重建PDGF B 依赖性通路，可以恢复衰老的心脏血管生成功能。 此外，这种促血管生成途径可以保护衰老的心脏免遭心肌梗塞。 总而言之，这些初步数据有力地支持了以下假设：在源自老化骨髓的 EPC 中重建 PDGF B 诱导的通路将恢复衰老的心脏血管生成功能。该项目的长期目标是通过分子恢复源自衰老骨髓的 EPC 的活性，特异性增强衰老心脏中的血管生成活性。 PDGF B 诱导上游通路的关键元件将在较老的骨髓来源的 EPC 中得到定义和恢复，以促进衰老心脏促血管生成通路的长期重建。 此外，介导PDGF B诱导的血管生成作用的关键下游基因组将被定义为建立分子治疗方案的手段，以限制衰老的骨髓源性EPC对心脏血管系统的促血管生成功能的恢复。 这些研究确定的元素和基因的生理意义将取决于它们促进心脏血管生成功能和保护衰老心脏免受心肌梗塞的能力。 总体而言，该研究计划将为开发新方法奠定基础，以开发源自老化骨髓的 EPC 的潜力，用于治疗和可能预防老年人的心血管疾病。